High titers of autoantibodies to glutamate decarboxylase in type 1 diabetes patients: epitope analysis and inhibition of enzyme activity.

OBJECTIVE: Autoantibodies to glutamate decarboxylase (GAD65Ab) are found in patients with autoimmune neurological disorders or type 1 diabetes. The correct diagnosis of GAD65Ab-associated neurological disorders is often delayed by the variability of symptoms and a lack of diagnostic markers. We hypothesized that the frequency of neurological disorders with high GAD65Ab titers is significantly higher than currently recognized. METHODS: We analyzed GAD65Ab titer, GAD65 enzyme activity inhibition, and GAD65Ab epitope pattern in a cohort of type 1 diabetes patients (n = 100) and correlated our findings with neurological symptoms and diseases. RESULTS: Overall, 43% (43/100) of patients had detectable GAD65Ab titers (median = 400 U/mL, range: 142-250,000 U/mL). The GAD65Ab titers in 10 type 1 diabetes patients exceeded the 90th percentile of the cohort (2,000-250,000 U/mL). Sera of these 10 patients were analyzed for their GAD65Ab epitope specificity and their ability to inhibit GAD65 enzyme activity in vitro. GAD65Ab of 5 patients inhibited the enzyme activity significantly (by 34-55%). Three patients complained of muscle stiffness and pain, which was documented in 2 of these patients. CONCLUSIONS: Based on our findings, we suggest that neurological disorders with high GAD65Ab titers are more frequent in type 1 diabetes patients than currently recognized.

Fanconi's syndrome and nephrogenic diabetes insipidus in an adult treated with ifosfamide.

Fanconi's syndrome is a serious condition characterized by type II proximal renal tubular dysfunction, with urinary loss of glucose, amino acids, phosphate, bicarbonate, and potassium. Ifosfamide-induced Fanconi's syndrome is reported in about 1.4-5% of children being treated for solid tumors, yet only a few cases have been reported in adults. We describe a 54-year-old man who came to the hospital with symptoms of neutropenic fever 4 days after his fourth cycle of ifosfamide and doxorubicin treatment for recurrent sarcoma with metastases to the lung. During admission, he was noted to have severe renal tubular dysfunction; ifosfamide-induced nephrogenic diabetes insipidus and Fanconi's syndrome were suspected. He received supportive therapy that resulted in incomplete resolution of signs and symptoms. The patient was discharged after a 5-day hospital stay when his white blood cell count increased from 0.1-2.5 × 10(3) /mm(3) and his fever had resolved. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of diabetes insipidus and Fanconi's syndrome and his use of ifosfamide. This dual diagnosis of diabetes insipidus and Fanconi's syndrome in an adult makes this case unusual, as well as therapeutically challenging. We conducted a review of the existing literature regarding ifosfamide-induced Fanconi's syndrome and describe the proposed mechanisms and therapeutic options. This case suggests that patients treated with ifosfamide should be monitored closely for renal function to identify, and perhaps prevent, these rare adverse events. Preliminary animal models show promise for adding N-acetylcysteine to ifosfamide treatment, but more research is necessary before using this drug as a therapeutic option.

Insulin glargine or neutral protamine Hagedorn in patients with severe insulin resistance: Is there a benefit?

OBJECTIVE: To determine the benefit of neutral protamine Hagedorn (NPH) insulin compared with insulin glargine in a patient with type 2 diabetes mellitus and severe insulin resistance. METHODS: We describe the patient's clinical findings and treatment course. RESULTS: A 52-year-old man with a 3-year history of type 2 diabetes mellitus did not achieve adequate glucose control despite escalation of his treatment regimen to insulin glargine, 80 units twice daily; insulin lispro, 60 units before each meal; and metformin. Dietary and lifestyle changes were emphasized and implemented while medication adherence with appropriate insulin technique was reviewed at each visit. Insulin glargine was replaced with the same dosage of NPH insulin. After 3 months, a significant drop in hemoglobin A1c was noted, from 9.5% to 6.1%, consistent with the improved capillary glucose measurements. The effect was maintained over the following year, without any major hypoglycemic events. CONCLUSION: NPH insulin might be superior to the long-acting analogue insulin glargine in cases of severe insulin resistance, but randomized studies are needed to confirm our finding and clarify the involved mechanisms.